The overall objective of the current SCOR and the PROPOSED RENEWAL is to elucidate the molecular basis for the long-term adaptive response of the heart to injury, both inherited and acquired, whether manifested by hypertrophy or dilitation. In Project 3 we focus on the paradigm of dilated cardiomyopathy with arrhythmias affecting primarily the right ventricle. Arrhythmogenic right ventricular dysplasia (ARVD), is a familial cardiomyopathy of unknown etiology characterized by a gradual loss of myocytes and replacement by fatty and fibrous tissue which, as it progresses, leads to dilitation of the right ventricle and impaired cardiac function. Thus, ARVD is initiated in the right ventricle in contrast to FDCM which is initiated in the left ventricle. The pathology of ARVD extends from the right ventricle to involve the left ventricle which is a mirror image to both the initial site of involvement and the spread of pathology observed in FDCM. The clinical course is characterized by arrhythmias, sudden death, and heart failure, process whereby myocardial cells die and are replaced by fatty-fibrous tissue is due to apoptosis Although four genetic loci are associated with this disease, none of the causative genes have been identified. We propose to identify the gene responsible for ARVD in our family which we recently mapped to a novel loci, 3p23, using either a positional candidate or positional cloning approach. We will use physical mapping information available on the World Wide Web to identify YAC clones and ESTs which map to the critical regions. We will use this cloned material to identify new genetic markers to further delineate the region as well as new candidate genes to be sequenced in our families. We further propose to map a novel locus in a family we have identified that is not linked to any known ARVD locus and ultimately to identify that gene as well. These objectives address the general hypothesis that identifying genetic defects and unraveling the molecular basis for familial cardiomyopathies will provide insight fundamental to the understanding of ventricular failure observed in response to a variety of other familial and acquired diseases. Additionally, unraveling the chamber specific stimuli or gene that localizes and determines the ventricular response in the right as opposed to the left ventricle and elucidating the role of apoptosis in heart remodeling will have important implications for the pathogenesis and treatment of heart failure.